Intraluminal stent

ABSTRACT

An intraluminal stent comprising fibrin is capable of reducing the incidence of restenosis at the site of vascular injury such as that produced by an angioplasty procedure.

This is a continuation of application Ser. No. 07/854,118 filed on Mar.19, 1992, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a method for lessening restenosis of bodylumens and to intraluminal stents having anti-thrombosis andanti-restenosis properties.

Restenosis is the closure of a peripheral or coronary artery followingtrauma to the artery caused by efforts to open an occluded portion ofthe artery, such as, for example, by dilation, ablation, atherectomy orlaser treatment of the artery. For these angioplasty procedures,restenosis occurs at a rate of about 20-50% depending on the vessellocation, lesion length and a number of other variables. Restenosis isbelieved to be a natural healing reaction to the injury of the arterialwall that is caused by angioplasty procedures. The healing reactionbegins with the clotting of blood at the site of the injury. The finalresult of the complex steps of the healing process is intimalhyperplasia, the migration and proliferation of medial smooth musclecells, until the artery is again stenotic or occluded.

In an attempt to prevent restenosis, metallic intravascular stents havebeen permanently implanted in coronary or peripheral vessels. The stentis typically inserted by catheter into a vascular lumen and expandedinto contact with the diseased portion of the arterial wall, therebyproviding internal support for the lumen. However, it has been foundthat restenosis can still occur with such stents in place. Also, thestent itself can cause undesirable local thrombosis. To address theproblem of thrombosis, persons receiving stents also receive extensivesystemic treatment with anticoagulant and antiplatelet drugs.

To address the restenosis problem, it has been proposed to providestents which are seeded with endothelial cells (Dichek, D. A. et alSeeding of Intravascular Stents With Genetically Engineered EndothelialCells; Circulation 1989; 80:1347-1353). In that experiment, sheependothelial cells that had undergone retrovirus-mediated gene transferfor either bacterial beta-galactosidase or human tissue-type plasmogenactivator were seeded onto stainless steel stents and grown until thestents were covered. The cells were therefore able to be delivered tothe vascular wall where they could provide therapeutic proteins. Othermethods of providing therapeutic substances to the vascular wall bymeans of stents have also been proposed such as in international patentapplication WO 91/12779 "Intraluminal Drug Eluting Prosthesis" andinternational patent application WO 90/13332 "Stent With Sustained DrugDelivery". In those applications, it is suggested that antiplateletagents, anticoagulant agents, antimicrobial agents, antimetabolic agentsand other drugs could be supplied in stents to reduce the incidence ofrestenosis.

In the vascular graft art, it has been noted that fibrin can be used toproduce a biocompatible surface. For example, in an article by Soldaniet al., "Bioartificial Polymeric Materials Obtained from Blends ofSynthetic Polymers with Fibrin and Collagen" International Journal ofArtificial Organs, Vol. 14, No. 5, 1991, polyurethane is combined withfibrinogen and cross-linked with thrombin and then made into vasculargrafts. In vivo tests of the vascular grafts reported in the articleindicated that the fibrin facilitated tissue ingrowth and was rapidlydegraded and reabsorbed. Also, in published European Patent Application0366564 applied for by Terumo Kabushiki Kaisha, Tokyo, Japan, disclosesa medical device such as an artificial blood vessel, catheter orartificial internal organ is made from a polymerized protein such asfibrin. The fibrin is said to be highly nonthrombogenic and tissuecompatible and promotes the uniform propagation of cells thatregenerates the intima. Also, in an article by Gusti et al., "NewBiolized Polymers for Cardiovascular Applications", Life SupportSystems, Vol. 3, Suppl. 1, 1986, "biolized" polymers were made by mixingsynthetic polymers with fibrinogen and cross-linking them with thrombinto improve tissue ingrowth and neointima formation as the fibrinbiodegrades. Also, in an article by Haverich et al., "Evaluation ofFibrin Seal in Animal Experiments", Thoracic Cardiovascular Surgeon,Vol. 30, No. 4, pp. 215-22, 1982, the authors report the successfulsealing of vascular grafts with fibrin. However, none of these teachthat the problem of restenosis could be addressed by the use of fibrinand, in fact, conventional treatment with anticoagulant drugs followingangioplasty procedures is undertaken because the formation of bloodclots (which include fibrin) at the site of treatment is thought to beundesirable.

SUMMARY OF THE INVENTION

I have found that an intraluminal stent comprising fibrin is capable ofreducing the incidence of restenosis at the site of a vascular injuryand can also serve as a matrix for the local administration of drugs tothe site of a vascular injury. Fibrin is a naturally occurringbioabsorbable polymer of fibrinogen that arises during bloodcoagulation. As set forth above, antiplatelet and anticoagulant agentsare thought to be desirable to prevent thrombosis (and to therebyprevent fibrin formation) in the lumen at the site of dilation or othertreatment. By contrast, I have found that providing fibrin at the siteof treatment can provide a readily tolerated, bioabsorbable surfacewhich will interact in a natural manner with the body's healingmechanism and reduce the prospect for the intimal hyperplasia thatcauses restenosis.

A stent according to the present invention can be made in virtually anyconfiguration and can be delivered conventionally by catheter to thesite of the luminal closure or restriction. A method for making such astent and a method for treating restenosis with fibrin is alsodisclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a elevational view of a balloon catheter with a metallic stentincluding a fibrin coating according to the present invention.

FIG. 2 is a elevational view of a balloon catheter with a metallic stentincluding a fibrin film according to the present invention.

FIG. 3 is an elevational view of a polymeric stent incorporating fibrinaccording to the present invention.

FIGS. 4-10 illustrate a method of making a stent according to thepresent invention. FIG. 4 is an elevational view of a stent and rigidtube into which the stent is inserted. FIG. 5 is an elevational view ofthe tube of FIG. 4 into which a catheter balloon is inserted.

FIG. 6 is partial sectional view of the tube of FIG. 5 with includedstent and catheter.

FIG. 7 is a partial sectional view of the tube of FIG. 6 to which fibrinhas been added.

FIG. 8 is a partial sectional view of the tube of FIG. 7 in which theballoon has been expanded.

FIG. 9 is an elevational view of the resulting stent being removed fromthe tube of FIG. 8.

FIG. 10 is an elevational view of the completed stent mounted on theballoon of a catheter.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stent comprising fibrin. The term"fibrin" herein means the naturally occurring polymer of fibrinogen thatarises during blood coagulation.

Blood coagulation generally requires the participation of several plasmaprotein coagulation factors: factors XII, XI, IX, X, VIII, VII, V, XIII,prothrombin, and fibrinogen, in addition to tissue factor (factor III),kallikrein, high molecular weight kininogen, Ca⁺², and phospholipid. Thefinal event is the formation of an insoluble, cross-linked polymer,fibrin, generated by the action of thrombin on fibrinogen. Fibrinogenhas three pairs of polypeptide chains (ALPHA 2--BETA 2--GAMMA 2)covalently linked by disulfide bonds with a total molecular weight ofabout 340,000. Fibrinogen is converted to fibrin through proteolysis bythrombin. An activation peptide, fibrinopeptide A (human) is cleavedfrom the amino-terminus of each ALPHA chain; fibrinopeptide B (human)from the amino-terminus of each BETA chain. The resulting monomerspontaneously polymerizes to a fibrin gel. Further stabilization of thefibrin polymer to an insoluble, mechanically strong form, requirescross-linking by factor XIII. Factor XIII is converted to XIIIa bythrombin. XIIIa cross-links the GAMMA chains of fibrin bytransglutaminase activity, forming EPSILON--(GAMMA--lutamyl) lysinecross-links. The ALPHA chains of fibrin also may be cross-linked.

Since fibrin blood clots are naturally subject to fibrinolysis as partof the body's repair mechanism, implanted fibrin can be rapidlybiodegraded. Plasminogen is a circulating plasma protein that isadsorbed onto the surface of the fibrin polymer. The adsorbedplasminogen is converted to plasmin by plasmogen activator released fromthe vascular endothelium. The plasmin will then break down the fibrininto a collection of soluble peptide fragments.

Methods for making fibrin and forming it into implantable devices arewell known as set forth in the following patents and publishedapplications which are hereby incorporated by reference. In U.S. Pat.No. 4,548,736 issued to Muller et al., fibrin is clotted by contactingfibrinogen with a fibrinogen-coagulating protein such as thrombin,reptilase or ancrod. Preferably, the fibrin in the fibrin-containingstent of the present invention has Factor XIII and calcium presentduring clotting, as described in U.S. Pat. No. 3,523,807 issued toGerendas, or as described in published European Patent Application0366564, in order to improve the mechanical properties and biostabilityof the implanted device. Also preferably, the fibrinogen and thrombinused to make fibrin in the present invention are from the same animal orhuman species as that in which the stent of the present invention willbe implanted in order to avoid cross-species autoimmune reactions. Inthe Muller patent, the fibrin product is in the form of a fine fibrinfilm produced by casting the combined fibrinogen and thrombin in a filmand then removing moisture from the film osmotically through a moisturepermeable membrane. In the European Patent Application 0366564, asubstrate (preferably having high porosity or high affinity for eitherthrombin or fibrinogen) is contacted with a fibrinogen solution and witha thrombin solution. The result is a fibrin layer formed bypolymerization of fibrinogen on the surface of the device. Multiplelayers of fibrin applied by this method could provide a fibrin layer ofany desired thickness. Or, as in the Gerendas patent, the fibrin canfirst be clotted and then ground into a powder which is mixed with waterand stamped into a desired shape in a heated mold. Increased stabilitycan also be achieved in the shaped fibrin by contacting the fibrin witha fixing agent such as glutaraldehyde or formaldehyde. These and othermethods known by those skilled in the art for making and forming fibrinmay be used in the present invention.

Preferably the coagulating effect of any residual coagulation protein inthe fibrin should be neutralized before employing it in the stent of thepresent invention in order to prevent clotting at the fibrin interfacewith blood after stent implantation. This can be accomplished, forexample, by treating the fibrin with irreversible coagulation inhibitorcompounds after polymerization. For example, hirudin orD-phenylalanyl-propyl-arginine chloromethyl ketone (PPACK) could beused. Anti-coagulants such as heparin can also be added to reduce thepossibility of further coagulation.

Polymeric materials can also be intermixed in a blend or co-polymer withthe fibrin to produce a material with the desired properties of fibrinwith improved structural strength. For example, the polyurethanematerial described in the article by Soldani et al., "BioartificialPolymeric Materials Obtained from Blends of Synthetic Polymers withFibrin and Collagen" International Journal of Artificial Organs, Vol.14, No. 5, 1991, which is incorporated herein by reference, could besprayed onto a suitable stent structure. Suitable polymers could also bebiogradeable polymers such as polyphosphate ester, polyhydroxybutyricvalerate (PHBV) and the like.

In U.S. Pat. No. 4,548,736 issued to Muller et al., a fibrin compositionis disclosed which can be a bioabsorbable matrix for delivery of drugsto a patient. Such a fibrin composition can also be used in the presentinvention by incorporating a drug or other therapeutic substance usefulin diagnosis or treatment of body lumens to the fibrin provided on thestent. The drug, fibrin and stent can then be delivered to the portionof the body lumen to be treated where the drug may elute to affect thecourse of restenosis in surrounding luminal tissue. Examples of drugsthat are thought to be useful in the treatment of restenosis aredisclosed in published international patent application WO 91/12779"Intraluminal Drug Eluting Prosthesis" which is incorporated herein byreference. Therefore, useful drugs for treatment of restenosis and drugsthat can be incorporated in the fibrin and used in the present inventioncan include drugs such as anticoagulant drugs, antiplatelet drugs,antimetabolite drugs, anti-inflammatory drugs and antimitotic drugs.Such therapeutic substances can also be microencapsulated prior to theirinclusion in the fibrin. The micro-capsules then control the rate atwhich the therapeutic substance is provided to the blood stream or thebody lumen. This avoids the necessity for dehydrating the fibrin as setforth in Muller et al., since a dense fibrin structure would not berequired to contain the therapeutic substance and limit the rate ofdelivery from the fibrin. For example, a suitable fibrin matrix for drugdelivery can be made by adjusting the pH of the fibrinogen to belowabout pH 6.7 in a saline solution to prevent precipitation (e.g., NaCl,CaCl, etc.), adding the microcapsules, treating the fibrinogen withthrombin and mechanically compressing the resulting fibrin into a thinfilm. The microcapsules which are suitable for use in this invention arewell known. For example, the disclosures of U.S. Pat. Nos. 4,897,268,4,675,189; 4,542,025; 4,530,840; 4,389,330; 4,622,244; 4,464,317; and4,943,449 could be used and are incorporated herein by reference.

The term "stent" herein means any device which when placed into contactwith a site in the wall of a lumen to be treated, will also place fibrinat the lumen wall and retain it at the lumen wall. This can includeespecially devices delivered percutaneously to treat coronary arteryocclusions and to seal dissections or aneurysms of splenic, carotid,iliac and popliteal vessels. The stent can also have underlyingpolymeric or metallic structural elements onto which the fibrin isapplied or the stent can be a composite of fibrin intermixed with apolymer. For example, a deformable metal wire stent such as thatdisclosed in U.S. Pat. No. 4,886,062 issued to Wiktor could be coatedwith fibrin as set forth above in one or more coats (i.e polymerizationof fibrin on the metal framework by application of a fibrinogen solutionand a solution of a fibrinogen-coagulating protein) or provided with anattached fibrin preform such as an encircling film of fibrin made as setforth above (i.e a cast film as set forth in the Muller et al. patent).The stent and fibrin could then be placed onto the balloon at a distalend of a balloon catheter and delivered by conventional percutaneousmeans (e.g. as in an angioplasty procedure) to the site of therestriction or closure to be treated where it would then be expandedinto contact with the body lumen by inflating the balloon. The cathetercan then be withdrawn, leaving the fibrin stent of the present inventionin place at the treatment site. The stent may therefore provide both asupporting structure for the lumen at the site of treatment and also astructure supporting the secure placement of fibrin at the lumen wall.FIG. 1 shows a stent having this general construction in place on aballoon catheter. A catheter 10 has a balloon 15 upon which a stent 20has been placed, the stent 20 having a deformable metal portion 22 and afibrin coating 24 thereon. FIG. 2 shows an alternative stent 30 in whicha fibrin film 32 has been affixed to the underlying metallic framework34 by affixing it to the stent 30 by e.g. wrapping the film 32 aroundthe framework 34 and securing the film 32 to the framework 34 (e.g. withan adhesive material) so that the film 32 will stay on the balloon 36and framework 34 until it is delivered to the site of treatment. Thefilm 32 is preferably wrapped over the framework 34 with folds orwrinkles that will allow the stent 30 to be readily expanded intocontact with the wall of the lumen to be treated.

Also, for example, a self-expanding stent of resilient polymericmaterial such as that disclosed in published international patentapplication WO 91/12779 "Intraluminal Drug Eluting Prosthesis" could beused in which fibrin is coated onto the stent or incorporated within thepolymeric material of the stent. A stent of this general configurationis shown in FIG. 3. The stent 40 has a first set of filaments 42 whichare helically wound in one direction and a second set of filaments 44which are helically wound in a second direction. Any or all of thesefilaments 42, 44 could be fibrin and/or a blend of fibrin with anotherpolymer. The combination of fibrin with another polymer may be preferredto provide improved mechanical properties and manufacturability for theindividual filaments 42, 44. A suitable material for fibrin-containingfilaments 42, 44 is the crosslinked blend of polyurethane and fibrinused as a vascular graft material in the article by Soldani et al.,"Bioartificial Polymeric Materials Obtained from Blends of SyntheticPolymers with Fibrin and Collagen" International Journal of ArtificialOrgans, Vol. 14, No. 5, 1991, which is incorporated herein by reference.Other biostable or bioerodeable polymers could also be used. Afibrin-containing stent of this configuration can be affixed to thedistal end of a catheter in a longitudinally stretched condition whichcauses the stent to decrease in diameter. The stent is then deliveredthrough the body lumen on the catheter to the treatment site where thestent is released from the catheter to allow it to expand into contactwith the lumen wall. It will be apparent to those skilled in the artthat other self-expanding stent designs (such as resilient metal stentdesigns) could also be used with fibrin either incorporated in thematerial of the underlying structure of the stent or coated on theunderlying structure of the stent.

A preferred method of making a stent according to the present inventionis as set forth in FIGS. 4-10. A stent 50 of the type disclosed in U.S.Pat. No. 4,886,062 issued to Wiktor is inserted into a tube 55 which ispreferably made from a rigid material and which has an inside diameterwhich is large enough to accommodate an unexpanded PTCA balloon butwhich is smaller than a fully inflated PTCA balloon. A PTCA balloon 60attached to a catheter 62 and inflation device (not shown) is insertedinto the stent 50 and tube 55. Fibrinogen at a pH of about 6.5,suspended in a saline solution, and thrombin are inserted into the tube55 around the deflated balloon 60 and stent 50. The amount of thrombinadded is not critical but preferably will polymerize the fibrinogen tofibrin 65 in about 5 minutes. After polymerization, the fibrin isallowed to crosslink for about an hour. The balloon 60 is then inflatedto compress the fibrin 65 between the balloon 60 and tube 55. Theballoon 60 is then deflated and removed from the tube 55. The resultingfibrin stent 70 includes the stent 50 embedded in a very thin elasticfilm of fibrin 65. The fibrin stent 70 may then be removed from the tube55 and washed in a buffered saline solution. Further processing of thefibrin stent can also be undertaken to neutralize thrombin with PPACK orhirudin; to add anticoagulants such as heparin; to further facilitatecrosslinking by incubation at body temperature in a biological buffersuch as a solution of blood serum buffered by4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES); or to addplasticizers such as glycerol. The resulting fibrin stent can then beplaced over a balloon, and secured onto the balloon by crimping. Thestent can then be delivered transluminally and expanded into place inthe body lumen by conventional procedures.

In a variant of this procedure, the metal stent portion may beeliminated to make a fibrin tube which can be placed on a ballooncatheter and expanded into place in a body lumen. The absence ofpermanently implanted metal elements would allow the entire stent tobiodegrade as healing is completed in the body lumen.

It will be appreciated by those skilled in the art that while theinvention has been described above in connection with particularembodiments the invention is not necessarily so limited and thatnumerous other embodiments, uses, modifications and departures from theembodiments, and uses may be made without departing from the inventiveconcepts.

I claim:
 1. An intraluminal stent for implantation in a body lumen, inwhich the stent has a surface adapted to be retained in contact with awall of the body lumen, the stent comprising a pre-formed fibrin film onthe lumen-contacting surface thereof, said fibrin provided by contactingfibrinogen with a fibrinogen-coagulating protein, and wherein the fibrinis intermixed with a polymeric material.